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Neurodegenerative diseases are characterized by selective vulnerability of distinct cell populations; however, the cause for this specificity remains elusive. Here, we show that entorhinal cortex layer 2 (EC2) neurons are unusually vulnerable to prolonged neuronal inactivity compared with neighboring regions of the temporal lobe, and that reelin + stellate cells connecting EC with the hippocampus are preferentially susceptible within the EC2 population. We demonstrate that neuronal death after silencing can be elicited through multiple independent means of activity inhibition, and that preventing synaptic release, either alone or in combination with electrical shunting, is sufficient to elicit silencing-induced degeneration. Finally, we discovered that degeneration following synaptic silencing is governed by competition between active and inactive cells, which is a circuit refinement process traditionally thought to end early in postnatal life. Our data suggests that the developmental window for wholesale circuit plasticity may extend into adulthood for specific brain regions. We speculate that this sustained potential for remodeling by entorhinal neurons may support lifelong memory but renders them vulnerable to prolonged activity changes in disease., Competing Interests: RZ, SG, CW, GP, MC, ML, AS, KP, JJ No competing interests declared, (© 2022, Zhao, Grunke, Wood et al.)

Numerous aggregation inhibitors have been developed with the goal of blocking or reversing toxic amyloid formation in vivo. Previous studies have used short peptide inhibitors targeting different amyloid β (Aβ) amyloidogenic regions to prevent aggregation. Despite the specificity that can be achieved by peptide inhibitors, translation of these strategies has been thwarted by two key obstacles: rapid proteolytic degradation in the bloodstream and poor transfer across the blood-brain barrier. To circumvent these problems, we have created a minigene to express full-length Aβ variants in the mouse brain. We identify two variants, F20P and F19D/L34P, that display four key properties required for therapeutic use: neither peptide aggregates on its own, both inhibit aggregation of wild-type Aβ in vitro, promote disassembly of pre-formed fibrils, and diminish toxicity of Aβ oligomers. We used intraventricular injection of adeno-associated virus (AAV) to express each variant in APP/PS1 transgenic mice. Lifelong expression of F20P, but not F19D/L34P, diminished Aβ levels, plaque burden, and plaque-associated neuroinflammation. Our findings suggest that AAV delivery of Aβ variants may offer a novel therapeutic strategy for Alzheimer's disease. More broadly our work offers a framework for identifying and delivering peptide inhibitors tailored to other protein-misfolding diseases., Competing Interests: Declaration of interests K.-W.P. completed the bulk of this study while employed at Baylor College of Medicine performing work that was fully funded by NIH and a non-profit research foundation. In July 2020, K.-W.P. left Baylor to become CEO of Aβrain, a biotechnology company he founded to pursue AAV-based therapeutics for protein aggregation disorders. He is currently a paid employee and sole owner of Aβrain. The other authors declare no competing interests., (Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Type I interferon (IFN) is a key cytokine that curbs viral infection and cell malignancy. Previously, we demonstrated a potent IFN immunogenicity of nucleic acid-containing (NA-containing) amyloid fibrils in the periphery. Here, we investigated whether IFN is associated with β-amyloidosis inside the brain and contributes to neuropathology. An IFN-stimulated gene (ISG) signature was detected in the brains of multiple murine Alzheimer disease (AD) models, a phenomenon also observed in WT mouse brain challenged with generic NA-containing amyloid fibrils. In vitro, microglia innately responded to NA-containing amyloid fibrils. In AD models, activated ISG-expressing microglia exclusively surrounded NA+ amyloid β plaques, which accumulated in an age-dependent manner. Brain administration of rIFN-β resulted in microglial activation and complement C3-dependent synapse elimination in vivo. Conversely, selective IFN receptor blockade effectively diminished the ongoing microgliosis and synapse loss in AD models. Moreover, we detected activated ISG-expressing microglia enveloping NA-containing neuritic plaques in postmortem brains of patients with AD. Gene expression interrogation revealed that IFN pathway was grossly upregulated in clinical AD and significantly correlated with disease severity and complement activation. Therefore, IFN constitutes a pivotal element within the neuroinflammatory network of AD and critically contributes to neuropathogenic processes.

An early hallmark of Alzheimer's disease is the accumulation of amyloid-β (Aβ), inspiring numerous therapeutic strategies targeting this peptide. An alternative approach is to destabilize the amyloid beta precursor protein (APP) from which Aβ is derived. We interrogated innate pathways governing APP stability using a siRNA screen for modifiers whose own reduction diminished APP in human cell lines and transgenic Drosophila. As proof of principle, we validated PKCβ-a known modifier identified by the screen-in an APP transgenic mouse model. PKCβ was genetically targeted using a novel adeno-associated virus shuttle vector to deliver microRNA-adapted shRNA via intracranial injection. In vivo reduction of PKCβ initially diminished APP and delayed plaque formation. Despite persistent PKCβ suppression, the effect on APP and amyloid diminished over time. Our study advances this approach for mining druggable modifiers of disease-associated proteins, while cautioning that prolonged in vivo validation may be needed to reveal emergent limitations on efficacy., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Drug development for Alzheimer's disease has endeavored to lower amyloid β (Aβ) by either blocking production or promoting clearance. The benefit of combining these approaches has been examined in mouse models and shown to improve pathological measures of disease over single treatment; however, the impact on cellular and cognitive functions affected by Aβ has not been tested. We used a controllable APP transgenic mouse model to test whether combining genetic suppression of Aβ production with passive anti-Aβ immunization improved functional outcomes over either treatment alone. Compared with behavior before treatment, arresting further Aβ production (but not passive immunization) was sufficient to stop further decline in spatial learning, working memory, and associative memory, whereas combination treatment reversed each of these impairments. Cognitive improvement coincided with resolution of neuritic dystrophy, restoration of synaptic density surrounding deposits, and reduction of hyperactive mammalian target of rapamycin signaling. Computational modeling corroborated by in vivo microdialysis pointed to the reduction of soluble/exchangeable Aβ as the primary driver of cognitive recovery., (© 2018 Chiang et al.)

Despite increasing appreciation that oligomeric amyloid-β (Aβ) may contribute to cognitive decline of Alzheimer disease, defining the most critical forms has been thwarted by the changeable nature of these aggregates and the varying methods used for detection. Herein, using a broad approach, we quantified Aβ oligomers during the evolution of cognitive deficits in an aggressive model of Aβ amyloidosis. Amyloid precursor protein/tetracycline transactivator mice underwent behavioral testing at 3, 6, 9, and 12 months of age to evaluate spatial learning and memory, followed by histologic assessment of amyloid burden and biochemical characterization of oligomeric Aβ species. Transgenic mice displayed progressive impairments in acquisition and immediate recall of the trained platform location. Biochemical analysis of cortical extracts from behaviorally tested mice revealed distinct age-dependent patterns of accumulation in multiple oligomeric species. Dot blot analysis demonstrated that nonfibrillar Aβ oligomers were highly soluble and extracted into a fraction enriched for extracellular proteins, whereas prefibrillar species required high-detergent conditions to retrieve, consistent with membrane localization. Low-detergent extracts tested by 82E1 enzyme-linked immunosorbent assay confirmed the presence of bona fide Aβ oligomers, whereas immunoprecipitation-Western blotting using high-detergent extracts revealed a variety of SDS-stable low-n species. These findings show that different Aβ oligomers vary in solubility, consistent with distinct localization, and identify nonfibrillar Aβ oligomer-positive aggregates as tracking most closely with cognitive decline in this model., (Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is behaviorally identified by progressive memory impairment and pathologically characterized by the triad of β-amyloid plaques, neurofibrillary tangles, and neurodegeneration. Genetic mutations and risk factors have been identified that are either causal or modify the disease progression. These genetic and pathological features serve as basis for the creation and validation of mouse models of AD. Efforts made in the past quarter-century have produced over 100 genetically engineered mouse lines that recapitulate some aspects of AD clinicopathology. These models have been valuable resources for understanding genetic interactions that contribute to disease and cellular reactions that are engaged in response. Here we focus on mouse models that have been widely used stalwarts of the field or that are recently developed bellwethers of the future. Rather than providing a summary of each model, we endeavor to compare and contrast the genetic approaches employed and to discuss their respective advantages and limitations. We offer a critical account of the variables which may contribute to inconsistent findings and the factors that should be considered when choosing a model and interpreting the results. We hope to present an insightful review of current AD mouse models and to provide a practical guide for selecting models best matched to the experimental question at hand.

Anti-Aβ clinical trials are currently under way to determine whether preventing amyloid deposition will be beneficial in arresting progression of Alzheimer disease. Both clinical and preclinical studies suggest that antiamyloid strategies are only effective if started at early stages of the disease process in a primary prevention strategy. Because this approach will be difficult to deploy, strategies for secondary prevention aimed at later stages of disease are also needed. In this study, we asked whether combining innate immune activation in the brain with concurrent Aβ suppression could enhance plaque clearance and could improve pathologic outcomes in mice with moderate amyloid pathologic disorder. Starting at 5 months of age, tet-off amyloid precursor protein transgenic mice were treated with doxycycline (dox) to suppress further amyloid precursor protein/Aβ production, and at the same time mice were intracranially injected with adeno-associated virus 1 expressing murine IL-6 (AAV1-mIL-6). Three months later, mice treated with the combination of Aβ suppression and AAV1-mIL-6 showed significantly less plaque pathologic disorder than dox or AAV1-mIL-6 only groups. The combination of AAV1-mIL-6 + dox treatment lowered total plaque burden by >60% versus untreated controls. Treatment with either dox or AAV1-mIL-6 alone was less effective than the combination. Our results suggest a synergistic mechanism by which the up-regulation of mIL-6 was able to improve plaque clearance in the setting of Aβ suppression., (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Increasing evidence supports a role of neuroinflammation in the pathogenesis of Alzheimer's disease (AD). Previously, we identified a neuron-glia signaling pathway whereby Aβ acts as an upstream activator of astroglial nuclear factor kappa B (NF-κB), leading to the release of complement C3, which acts on the neuronal C3a receptor (C3aR) to influence dendritic morphology and cognitive function. Here we report that astrocytic complement activation also regulates Aβ dynamics in vitro and amyloid pathology in AD mouse models through microglial C3aR. We show that in primary microglial cultures, acute C3 or C3a activation promotes, whereas chronic C3/C3a treatment attenuates, microglial phagocytosis and that the effect of chronic C3 exposure can be blocked by cotreatment with a C3aR antagonist and by genetic deletion of C3aR. We further demonstrate that Aβ pathology and neuroinflammation in amyloid precursor protein (APP) transgenic mice are worsened by astroglial NF-κB hyperactivation and resulting C3 elevation, whereas treatment with the C3aR antagonist (C3aRA) ameliorates plaque load and microgliosis. Our studies define a complement-dependent intercellular cross talk in which neuronal overproduction of Aβ activates astroglial NF-κB to elicit extracellular release of C3. This promotes a pathogenic cycle by which C3 in turn interacts with neuronal and microglial C3aR to alter cognitive function and impair Aβ phagocytosis. This feedforward loop can be effectively blocked by C3aR inhibition, supporting the therapeutic potential of C3aR antagonists under chronic neuroinflammation conditions., Significance Statement: The complement pathway is activated in Alzheimer's disease. Here we show that the central complement factor C3 secreted from astrocytes interacts with microglial C3a receptor (C3aR) to mediate β-amyloid pathology and neuroinflammation in AD mouse models. Our study provides support for targeting C3aR as a potential therapy for Alzheimer's disease., (Copyright © 2016 the authors 0270-6474/16/360577-13$15.00/0.)

The accumulation of amyloid-β (Aβ) as amyloid fibrils and toxic oligomers is an important step in the development of Alzheimer's disease (AD). However, there are numerous potentially toxic oligomers and little is known about their neurological effects when generated in the living brain. Here we show that Aβ oligomers can be assigned to one of at least two classes (type 1 and type 2) based on their temporal, spatial, and structural relationships to amyloid fibrils. The type 2 oligomers are related to amyloid fibrils and represent the majority of oligomers generated in vivo, but they remain confined to the vicinity of amyloid plaques and do not impair cognition at levels relevant to AD. Type 1 oligomers are unrelated to amyloid fibrils and may have greater potential to cause global neural dysfunction in AD because they are dispersed. These results refine our understanding of the pathogenicity of Aβ oligomers in vivo., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Abnormal NFκB activation has been implicated in Alzheimer's disease (AD). However, the signaling pathways governing NFκB regulation and function in the brain are poorly understood. We identify complement protein C3 as an astroglial target of NFκB and show that C3 release acts through neuronal C3aR to disrupt dendritic morphology and network function. Exposure to Aβ activates astroglial NFκB and C3 release, consistent with the high levels of C3 expression in brain tissue from AD patients and APP transgenic mice, where C3aR antagonist treatment rescues cognitive impairment. Therefore, dysregulation of neuron-glia interaction through NFκB/C3/C3aR signaling may contribute to synaptic dysfunction in AD, and C3aR antagonists may be therapeutically beneficial., (Copyright © 2015 Elsevier Inc. All rights reserved.)

An unresolved debate in Alzheimer's disease (AD) is whether amyloid plaques are pathogenic, causing overt physical disruption of neural circuits, or protective, sequestering soluble forms of amyloid-β (Aβ) that initiate synaptic damage and cognitive decline. Few animal models of AD have been capable of isolating the relative contribution made by soluble and insoluble forms of Aβ to the behavioral symptoms and biochemical consequences of the disease. Here we use a controllable transgenic mouse model expressing a mutant form of amyloid precursor protein (APP) to distinguish the impact of soluble Aβ from that of deposited amyloid on cognitive function and synaptic structure. Rapid inhibition of transgenic APP modulated the production of Aβ without affecting pre-existing amyloid deposits and restored cognitive performance to the level of healthy controls in Morris water maze, radial arm water maze, and fear conditioning. Selective reduction of Aβ with a γ-secretase inhibitor provided similar improvement, suggesting that transgene suppression restored cognition, at least in part by lowering Aβ. Cognitive improvement coincided with reduced levels of synaptotoxic Aβ oligomers, greater synaptic density surrounding amyloid plaques, and increased expression of presynaptic and postsynaptic markers. Together these findings indicate that transient Aβ species underlie much of the cognitive and synaptic deficits observed in this model and demonstrate that significant functional and structural recovery can be attained without removing deposited amyloid., (Copyright © 2014 the authors 0270-6474/14/347871-15$15.00/0.)

Alzheimer's disease (AD) is associated with an elevated risk for seizures that may be fundamentally connected to cognitive dysfunction. Supporting this link, many mouse models for AD exhibit abnormal electroencephalogram (EEG) activity in addition to the expected neuropathology and cognitive deficits. Here, we used a controllable transgenic system to investigate how network changes develop and are maintained in a model characterized by amyloid β (Aβ) overproduction and progressive amyloid pathology. EEG recordings in tet-off mice overexpressing amyloid precursor protein (APP) from birth display frequent sharp wave discharges (SWDs). Unexpectedly, we found that withholding APP overexpression until adulthood substantially delayed the appearance of epileptiform activity. Together, these findings suggest that juvenile APP overexpression altered cortical development to favor synchronized firing. Regardless of the age at which EEG abnormalities appeared, the phenotype was dependent on continued APP overexpression and abated over several weeks once transgene expression was suppressed. Abnormal EEG discharges were independent of plaque load and could be extinguished without altering deposited amyloid. Selective reduction of Aβ with a γ-secretase inhibitor has no effect on the frequency of SWDs, indicating that another APP fragment or the full-length protein was likely responsible for maintaining EEG abnormalities. Moreover, transgene suppression normalized the ratio of excitatory to inhibitory innervation in the cortex, whereas secretase inhibition did not. Our results suggest that APP overexpression, and not Aβ overproduction, is responsible for EEG abnormalities in our transgenic mice and can be rescued independently of pathology.

Many new therapeutics for Alzheimer's disease delay the accumulation of amyloid-β (Aβ) in transgenic mice, but evidence for clearance of preexisting plaques is often lacking. Here, we demonstrate that anti-Aβ immunotherapy combined with suppression of Aβ synthesis allows significant removal of antecedent deposits. We treated amyloid-bearing tet-off APP (amyloid precursor protein) mice with doxycycline to suppress transgenic Aβ production before initiating a 12 week course of passive immunization. Animals remained on doxycycline for 3 months afterward to assess whether improvements attained during combined treatment could be maintained by monotherapy. This strategy reduced amyloid load by 52% and Aβ42 content by 28% relative to pretreatment levels, with preferential clearance of small deposits and diffuse Aβ surrounding fibrillar cores. We demonstrate that peripherally administered anti-Aβ antibody crossed the blood-brain barrier, bound to plaques, and was still be found associated with a subset of amyloid deposits many months after the final injection. Antibody accessed the brain independent of plasma Aβ levels, where it enhanced microglial internalization of aggregated Aβ. Our data support a mechanism by which passive immunization acts centrally to stimulate microglial phagocytosis of aggregated Aβ, but is opposed by the continued aggregation of newly secreted Aβ. By arresting the production of Aβ, combination therapy allows microglial clearance to work from a static amyloid burden toward a significant reduction in plaque load. Our findings suggest that combining two therapeutic approaches currently in clinical trials may improve neuropathological outcome over either alone.

Magnetic resonance (MR) imaging can provide a longitudinal view of neurological disease through repeated imaging of patients at successive stages of impairment. Until recently, the difficulty of manual delineation has limited volumetric analyses of MR data sets to a few select regions and a small number of subjects. Increased throughput offered by faster imaging methods, automated segmentation, and deformation-based morphometry have recently been applied to overcome this limitation with mouse models of neurological conditions. We use automated analyses to produce an unbiased view of volumetric changes in a transgenic mouse model for Alzheimer's disease (AD) at two points in the progression of disease: immediately before and shortly after the onset of amyloid formation. In addition to the cortex and hippocampus, where atrophy has been well documented in AD patients, we identify volumetric losses in the pons and substantia nigra where neurodegeneration has not been carefully examined. We find that deficits in cortical volume precede amyloid formation in this mouse model, similar to presymptomatic atrophy seen in patients with familial AD. Unexpectedly, volumetric losses identified by MR outside of the forebrain predict locations of future amyloid formation, such as the inferior colliculus and spinal nuclei, which develop pathology at very late stages of disease. Our work provides proof-of-principle that MR microscopy can expand our view of AD by offering a complete and unbiased examination of volumetric changes that guide us in revisiting the canonical neuropathology., (Copyright 2009 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is characterized by severe neuronal loss in several brain regions important for learning and memory. Of the structures affected by AD, the hippocampus is unique in continuing to produce new neurons throughout life. Mounting evidence indicates that hippocampal neurogenesis contributes to the processing and storage of new information and that deficits in the production of new neurons may impair learning and memory. Here, we examine whether the overproduction of amyloid-beta (Abeta) peptide in a mouse model for AD might be detrimental to newborn neurons in the hippocampus. We used transgenic mice overexpressing familial AD variants of amyloid precursor protein (APP) and/or presenilin-1 to test how the level (moderate or high) and the aggregation state (soluble or deposited) of Abeta impacts the proliferation and survival of new hippocampal neurons. Although proliferation and short-term survival of neural progenitors in the hippocampus was unaffected by APP/Abeta overproduction, survival of newborn cells 4 weeks later was dramatically diminished in transgenic mice with Alzheimer's-type amyloid pathology. Phenotypic analysis of the surviving population revealed a specific reduction in newborn neurons. Our data indicate that overproduction of Abeta and the consequent appearance of amyloid plaques cause an overall reduction in the number of adult-generated hippocampal neurons. Diminished capacity for hippocampal neuron replacement may contribute to the cognitive decline observed in these mice.

Background: The proteases (secretases) that cleave amyloid-beta (Abeta) peptide from the amyloid precursor protein (APP) have been the focus of considerable investigation in the development of treatments for Alzheimer disease. The prediction has been that reducing Abeta production in the brain, even after the onset of clinical symptoms and the development of associated pathology, will facilitate the repair of damaged tissue and removal of amyloid lesions. However, no long-term studies using animal models of amyloid pathology have yet been performed to test this hypothesis., Methods and Findings: We have generated a transgenic mouse model that genetically mimics the arrest of Abeta production expected from treatment with secretase inhibitors. These mice overexpress mutant APP from a vector that can be regulated by doxycycline. Under normal conditions, high-level expression of APP quickly induces fulminant amyloid pathology. We show that doxycycline administration inhibits transgenic APP expression by greater than 95% and reduces Abeta production to levels found in nontransgenic mice. Suppression of transgenic Abeta synthesis in this model abruptly halts the progression of amyloid pathology. However, formation and disaggregation of amyloid deposits appear to be in disequilibrium as the plaques require far longer to disperse than to assemble. Mice in which APP synthesis was suppressed for as long as 6 mo after the formation of Abeta deposits retain a considerable amyloid load, with little sign of active clearance., Conclusion: This study demonstrates that amyloid lesions in transgenic mice are highly stable structures in vivo that are slow to disaggregate. Our findings suggest that arresting Abeta production in patients with Alzheimer disease should halt the progression of pathology, but that early treatment may be imperative, as it appears that amyloid deposits, once formed, will require additional intervention to clear.

Epidemiological studies suggest that individuals with greater education or more cognitively demanding occupations have diminished risk of developing dementia. We wanted to test whether this effect could be recapitulated in rodents using environmental enrichment, a paradigm well documented to attenuate behavioral deficits induced by various pathological insults. Here, we demonstrate that learning and memory deficits observed in a transgenic mouse model of Alzheimer's disease can be ameliorated by enrichment. Female transgenic mice overexpressing amyloid precursor protein and/or presenilin-1 and nontransgenic controls were placed into enriched or standard cages at 2 months of age and tested for cognitive behavior after 6 months of differential housing. Enrichment significantly improved performance of all genotypes in the radial water maze and in the classic and repeated-reversal versions of the Morris water maze. However, enrichment did not benefit all genotypes equally. Mice overproducing amyloid-beta (Abeta), particularly those with amyloid deposits, showed weaker memory for the platform location in the classic Morris water maze and learned new platform positions in the repeated-reversals task less quickly than their nontransgenic cagemates. Nonetheless, enrichment normalized the performance of Abeta-overproducing mice to the level of standard-housed nontransgenic mice. Moreover, this functional preservation occurred despite increased neuritic plaque burden in the hippocampus of double-transgenic animals and elevated steady-state Abeta levels, because both endogenous and transgene-derived Abeta are increased in enriched animals. These results demonstrate that the generation of Abeta in vivo and its impact on the function of the nervous system can be strongly modulated by environmental factors.

More than 70 different mutations in presenilin 1 (PS1) have been associated with inherited early onset Alzheimer's disease (AD). How all these different mutations cause disease has not been clearly delineated. Our laboratory has previously shown that co-expression of mutant PS1 in mice transgenic for amyloid precursor protein (APPswe) dramatically accelerates the rate of amyloid deposition in the brain. In our original animals mutant PS1 was substantially over-expressed, and the stabilized pool of mouse PS1 fragments was largely replaced by the human protein. In this setting the accelerated amyloid pathology in the double transgenic mice could have been due, in part, to decreased endogenous PS1 activity. To investigate this possibility, we generated APP transgenic mice with reduced levels of endogenous PS1. We find that mice harboring only one functional PS1 allele and co-expressing Mo/HuAPPswe do not develop amyloid deposits at ages comparable to mice expressing mutant PS1. We next tested whether hypo-expression of mutant PS1 could accelerate the rate of amyloid deposition using an unusual line of transgenic mice expressing PS1dE9 at low levels, finding no significant acceleration. Our findings demonstrate that the accelerated amyloid pathology, caused by so many different mutations in PS1, is clearly not a result of haplo-insufficiency that might result from inactivating mutations. Instead, our data are consistent with a gain of property mechanism.

Epidemiological studies of Alzheimer patients from a wide variety of ethnic and socioeconomic backgrounds have identified education and occupation as environmental factors that can affect the risk of developing disease. A model of environmental manipulation in rodents uses enriched housing to provide cognitive and social stimulation. Previous studies have established elevations in synaptic number and function in rodents housed under enriched conditions. Recent experiments in hippocampal cultures have demonstrated that synaptic activity can influence the processing of amyloid precursor protein (APP). Here we examined whether changes in synaptic activity brought about by enriched housing might also influence the deposition of amyloid plaques in vivo using a transgenic mouse model of Alzheimer disease (AD). Mice co-expressing mutant APP and presenilin 1 (PS1) were housed in either enriched or standard cages from 2 months of age and then killed for pathological evaluation several months later. We find that, as compared to littermates housed in standard cages, the enriched APP/PS1 transgenic mice develop a higher amyloid burden with commensurate increases in aggregated and total A beta. These results suggest that A beta deposition can be exacerbated by the neuronal changes associated with enrichment, and demonstrate a substantial, albeit paradoxical, environmental influence on the progression of pathology in a mouse model of AD.